Carbon Based Multifunctional Nanomaterials for Biomedical Applications: A Brief Overview -Open Access Publishers
Carbon based nanomaterials (CBNs) serve as efficient
carries in drug delivery. Due to their high propensity to cross cell
membranes CNTs are identified as multipurpose innovative carriers in
drug delivery applications. The unique electronic and mechanical
properties of carbon based nanostructures can be tailored using
control-label chemical Functionalization. The potential long-term
toxicity concerns of CBNs are still not completely addressed. Innovative
ideas and solutions are required to develop carbon nanostructures based
efficient and economically viable biomaterials.
Keywords: Carbon based nanomaterials; Functionalization; Drug delivery; Multifunctional nanomaterials; Biomedical; Toxicity and safety Abbreviations: CNTs: Carbon Nanotubes; CBNs: Carbon Based Nanomaterials; SWNTs: Single Walled Carbon Nanotubes; AMB: Amphotericin B; AMBD: Amphotericin B With Sodium Deoxycholate
Introduction
Rapid advances in nanotechnology in the last two
decades aid in several fascinating developments in the health care
industry. Conventional surgical treatments are hindered by the
accessibility ofthe tumorous cells and damage risks in the vicinity of
vital organs. Also, selective chemotherapy and radiation techniques are
limited. In this context, nanomedicine provides a means of targeted drug
delivery. Since the dimensions of the biological body cells are of the
order of nanoscales, quantity of the drug required to cure the cells is
small. Due to the nanoscale dimensions of the carbon based nanomaterials
(CBNs), they can easily reach the body cells. Therefore, employing the
CNTs avoid additional solvents in the drug delivery. Thus, the disease
diagnosis and treatment process transformed painless in the recent
years.
Sp2 hybridized carbon based nanomaterials such as zero dimensional Fullerenes (0D) [1], one dimensional (1D) carbon nanotubes (CNTs) [2] and two dimensional (2D) graphene [3],
play a vital role in developing efficient biomaterials. Furthermore,
excellent mechanical, electrical and chemical characteristics of the
CBNs as well as their ability to hybridize with a wide range of organic
and inorganic materials preferred them in developing several novel and
efficient composite materials for various applications including
biomedical. Therefore, based on the multifunctional nature, CBNs are
promising in advanced biomedical applications. As a result, CBNs
attracted enormous interest of the materials research community.
Applications
Fullerenes and their derivatives can serve as drug
delivery vehicles. Under certain circumstances they act as nano-drugs as
well [4,5].
CNTs have been successfully employed in numerous applications,
including electronics, composite materials, fuel cells, sensors, optical
devices and biomedicine [6].
CNTs are identified as multipurpose innovative carriers in drug
delivery applications due to their high propensity to cross cell
membranes [7].
Because of high surface to volume ratios, CNTs are the prime choice in
drug de-livery. Various strategies developed to load small molecules
such as chemotherapeutic cancer drugs on CNTs via either covalent
conjugation , as non-covalent adsorption are explained in the schematic (Figure 1).
The photo-thermal therapy is a popular technique for
cancer treatments. Single walled carbon nanotubes (SWNTs) generate
significant amount of heat upon excitation with near-infrared light
(NIR, l=700-1100nm). Therefore, the photo-thermal effect can be employed
to induce thermal cell death in a noninvasive manner. Moon et al. [8] demonstrated the in vivo
obliteration of solid malignant tumors by the combined treatments of
SWNTs and NIR irradiation. Furthermore, the effect of electronic
structure (metallic versus semiconducting behaviour) of SWNTs in
regulating antimicrobial activity is studied in [9].
A permeable, single-walled carbon nanotube based filter for the
effective removal of bacterial and viral pathogens from water at low
pressures is proposed in [10].
While developing the filter, the authors used the key properties of
SWNTs, such as: small diameter and high surface area, tendency to
aggregate and form highly porous structures and the antibacterial
properties
Carbon nanotubes possess hydrophobic surfaces, which
are not soluble in aqueous solutions. Functionalizing CNTs with other
functional groups can make them hydrophilic. Functionalization is the
chemical process of attaching the functional groups to the CNT surfaces.
The unique electronic and mechanical properties of SWNTs can be
tailored using controllable chemical functionalization [6]. Benincasa et al. [11]
efficiently employed functionalized CNTs (f-CNTs) for the
transportation of micellar dispersed Amphotericin B (AMB) with sodium
deoxycholate (AMBD) in the treatment of serious invasive fungal
infections. The authors tested the antifungal activity of two conjugates
between f-CNTs and AMB, against a collection of reference and clinical
fungal strains, and reported that the measured minimum inhibition
concentrations for f-CNT-AMB conjugates are either comparable to or
better than those displayed by AMB and AMBD. Functionalized CNTs can be
also used as molecular carriers for in vitro and in vivo drug delivery,
primarily employed for cancer treatment [12].
Multiwalled carbon nanotubes (MWNTs), strongly
absorbs the near-infrared (nIR) radiation and efficiently convert
absorbed energy to released heat which can be used for localized
hyperthermia applications Ghosh et al. [13]
demonstrated that DNA-encasement increases heat emission following nIR
irradiation of MWNTs, and DNA-encased MWNTs can be used to safely
eradicate a tumor mass in vivo. They reported that DNA-encased MWNTs are
more efficient at converting nIR irradiation into heat compared to
nonencased MWNTs and hence, DNA-encased MWNTs can be used safely and
effectively for the selective thermal ablation of malignant tissue
in-vivo. A controlled drug release system for transporting Ibuprofen
using functionalized multiwall carbon nanotubes is discussed in [14]. Raffa et al. [7]
reported that length of nanotubes influence their uptake and shorter
(sub-1mm) MWNTs are easier to be internalized through an
energy-independent pathway.
CNTs are also employed in developing novel
bio-sensors to detect various biological targets and as nano-probes for
biomedical imaging [4,12,15]. Banerjee et al. [6]
explored the covalent chemical strategies for the functionalization of
carbon- nanotube surfaces. The authors reported their observations from a
structural perspective, the breadth and types of reactions SWNTs can
undergo in solution phase, not only at the ends and defect sites but
also along the sidewalls. Moreover, prevailing themes in nanotube
functionalization have been involved with dissolution of tubes. Su et
al. [16]
developed graphene quantum dot (GQD) based nanoprobe for targeted drug
delivery, sensing, dual-modal imaging and therapy, by conjugating the
carboxyl- terminated GQD with Fe3O4@SiO2 followed by functionalization with cancer targeting molecule folic acid. They reported a lumino magnetic Fe3O4@SiO2
@GQD-FA/DOX nanoprobe cancer diagnosis and therapy. A review of carbon
nanotubes for multifaceted applications in human healthcare industry is
available at [17].
Toxicity and safety issues
In biological applications, particularly in-vivo,
care must be taken to ensure that the toxicity of the nanomaterial is
thoroughly characterized and the material behavior is well understood.
The potential long-term toxicity concerns of CBNs are still not
completely addressed. Zhang et al. [18]
compared the cytotoxicity level of graphene to the CNTs in the neuronal
PC12 cells. They concluded that the toxicity depends on shape and
composition, where graphene is found to have a lower toxicity than CNTs.
However, subsequently the toxicity of Graphene is observed to be
inversely proportional to the concentration [19], In other words, graphene exhibits a higher toxicity at low concentrations compared to CNTs [19].
Further investigations on PEG-coated graphene nano sheets in mice and
subsequent photo-thermal treatment of cancerous tumors are reported
nontoxicity of graphene [20].
On the other hand, sharp Graphene nanosheet edges are observed to cause
considerable damage to the cell membrane of bacteria [21],
although the antibacterial property is useful. Moreover, compared to
hydrophobic pristine graphene, hydrophilic carboxyl-functionalized
Graphene are able to be internalized in cells without any toxic effects [22].
Wide ranges of morphologies, coatings and hybrid structures of graphene
sheets exists in the literature. However, detailed and long-term
studies are still required before the implementation
of important in-vivo biomedical applications.
Several reports, based on the experiments on animals [20,23,24], have suggested that well-functionalized CNTs and Graphene are safe within certain dosage. A few preliminary tests [22,25]
showcased that the CNTs are biologically benign to certain cells,
tissues, and organs under certain conditions. While further studies have
indicated that CNTs are potential hazards which can cause both acute
and chronic effects to many living systems [22].
However, the observation periods are generally no longer than six
months, which may not be sufficient to estimate the long-term safety
aspects of the CBNs. Therefore, the effect of the CBNs on the immune,
reproductive and nervous systems are yet to be systematically
investigated. In this context, pre-clinical toxicity studies are
required before adopting the carbon nanostructures based cancer
therapies can be finally translated into practice. Nevertheless, based
on the current knowledge, the biological effects of CNTs are observed to
be sample specific and must be assessed on a case-to-case basis.
Therefore, the nanotoxicity of CNTs requires continuous extensive
investigations by the regulatory bodies, before the CNTs can be used in
practice in functional biomaterials and biomedical devices.
Conclusions and future prospects
Carbon based nanostructures in drug delivery and bio
sensing applications, apart from the issues associated with toxicity and
safety in living biological systems, are addressed in this overview.
Intense research in the last two decades provided specificity,
selectivity, reproducibility and robustness to the carbon based
nanostructures for biological applications. As a result, carbon based
nanostructures are successfully applied in many areas of biomedical
research, like: drug delivery systems, tissue scaffold reinforcements
and cellular sensors [26].
Some of the parameters that influence the delivery performance of CBNs
include: shape and size, number of layers, removal of the catalyst
during synthesis, apart from the functionalization. However, toxicity of
CNTs and Graphene in living biological systems is still an issue to be
addressed at macroscopic, cellular and intracellular levels.
During the last decade, CBNs are extensively explored
as nanoscale drug carriers for potential applications in biomedicine
and cancer treatment. The unique physical properties of CBNs made them
the potential candidates in novel cancer therapies such as photo-thermal
therapy, photo acoustic therapy and radiofrequency (RF) ablation
treatment of tumours. Compared to traditional drug delivery systems,
such as biodegradable organic macromolecules, inorganic nanomaterials
like CNTs and Graphene may not have clear advantages when they are
exclusively used as drug carriers, as their degradation in the
biological systems is meager. However, the unique physical properties of
the sp2 hybridized CBNs enable a range of novel cancer therapies such
as photo thermal, photo acoustic and RF ablation, which could be
combined with therapeutic drugs and genes co-delivered by CNTs/Graphene,
overcoming the multidrug resistance problem in current cancer
chemotherapies for improved tumor treatment efficacy.
To summarize, we discussed the promising future
applications of CBNs for biomedicine, particularly: drug delivery,
tissue engineering and cancer therapy. The benefits of CBNs are
presented along with toxicity of CBNs and their harmful effects on
biological systems. There are many challenges that must be addressed
before CBNs can be integrated into the biomedical devices. The following
points are required to be addressed:
i. Advanced methodologies to increase the sensitivity of CBNs towards the single molecule detection.
ii. Efficient loading and unloading techniques for drug delivery to improve the overall performance of CBNs as carriers.
iii. Modification of CBNs to promote cell adhesion and growth.
iv. Experiments to accurately estimate the toxicity of cabon nanostructures based biomaterials.
Therefore, innovative ideas and solutions are
required to develop cabon nanostructures based efficient and
economically viable biomaterials.
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